It is known that dietary ingestion of creatine monohydrate is preferentially taken up by skeletal muscle. Indeed, creatine is used heavily as a dietary supplement for performance enhancement by athletes. This is because the creatine, once present muscle tissue where it is stored as creatine phosphate, reacts with adenosine diphosphate (ADP) to restore adenosine triphosphate (ATP) levels and provide energy needed for muscle activity. By ingesting creatine, athletes are able to load their muscle tissue with higher levels of creatine phosphate and are able to better sustain muscle activity.
Although many forms of creatine are stable ex vivo, including the creatine monohydrate and numerous esters, creatine and creatine monohydrate are known to be typically unstable in vivo, i.e., in the acidic environment that exists in the stomach, and the basic conditions of the lower gastrointestinal tract. So, for example, it is known that creatine monohydrate, which is a commonly ingested form of creatine, rapidly breaks down in the stomach to form creatinine. Furthermore, because creatine monohydrate is not easily fully solubilized in cold or room temperature water, it is often dissolved in fruit juices and other acidic liquids, which also promote degradation of creatine to creatinine and excretion. For these reasons, other forms of creatine, particularly creatine ethyl esters, have been the focus of product development. However, such compounds also suffer from solubility and degradation problems.
In an effort to create a stable form of creatine in which the creatine would be better protected from degradation while present in the stomach and intestines, tests were conducted in which polyethylene glycols were reacted with creatine in the presence of acid catalysts, including H2SO4, HCl and H3PO4. Although the temperature was varied from 20° C. to 100° C. using a wide variety of organic and mineral acid catalysts, the polyethylene creatine esters did not form in substantial quantities and/or degraded rapidly to creatinine. Moreover, the resulting creatine polyethylene esters did not exhibit a desired level of stability in low pH environments of the reaction mixture, analytical test methods or in stomach equivalent acidic environments.
Thereafter, the starting creatine component was first substituted with creatine monohydrate and thereafter with creatine HCl, with no improvement in production results.
To avoid degradation a different route was then chosen to produce an acceptable polyethylene glycol ester. Instead of using creatine as a starting material, creatine ethyl ester and creatine ethyl ester HCl were used as starting materials and reacted with polyethylene glycol under acid and alkaline conditions to trans-esterify the ethyl ester to creatine polyethylene glycol ester and ethanol. This approach yielded similar results in that the yield of creatine polyethylene glycol esters were again low and degraded rapidly to creatinine.
High-performance liquid chromatography (HPLC) test methods were used to test purities of the various starting materials and the desired polyethylene glycol ester. These test methods clearly showed the degradation of the creatine compounds to creatinine. In particular the ester compounds degraded faster than the starting materials of creatine, creatine monohydrate and creatine HCl. The test methods themselves also caused the creatine compounds to degrade as well during the test. Thin layer chromatography (TLC) was used with both alkaline and acidic mobile phases and showed similar results.
Other commercially available creatine esters, such as creatine ethyl ester and creatine ethyl ester HCl, were also tested for stability in low pH environments. Surprisingly, the ethyl esters, thought to be able to resist degradation better, were found to also degrade rapidly to creatinine, as did creatine, creatine monohydrate and creatine HCl.
The solubility and degradation problems associated with creatine typically result in low absorbance of ingested creatine. When absorbance is low, high doses must be taken to achieve desired levels in the blood and muscles. To accomplish this, a regimen of a creatine supplement of 20-30 grams per day is typically taken to compensate for the substantial loss of the creatine to degradation when dissolution and/or degraded by digestion into creatinine. Unfortunately, the presence of substantial amounts of creatinine in the digestive tract can cause digestive problems such as severe cramping, due to the toxic nature of creatinine.
Accordingly, development of a creatine formulation in which the creatine is in a form which is resistant to rapid degradation to creatinine, i.e., stable in acid and base environments of the stomach and gut, but which is ultimately absorbed with enhanced efficacy by skeletal muscle, remains needed.